The purpose of this paper is to describe potential improvements in patient safety resulting from design decisions in the development of a computerized decision support system (DSS) for managing opioid therapy for chronic noncancer pain. ATHENA-DSS is an automated decision support system developed in a collaboration between Stanford University and the U.S. Department of Veterans Affairs (VA) to increase guideline-adherent prescribing and to change physician behavior. Based on data in patients’ computerized medical record and knowledge of the clinical domain encoded in a knowledge base, the system gives patient-specific recommendations to primary care providers at the point of care. ATHENA-Opioid Therapy is based on a previous system, ATHENA-Hypertension, and is designed to follow the VA/Department of Defense clinical practice guideline for the management of opioid therapy for chronic noncancer pain. We describe the rationale for development of decision support system elements and a graphical user interface to increase patient safety during primary care treatment for chronic pain. The ATHENA-Opioid Therapy system focuses on reducing patient risk in four main ways by: (1) identifying patients with comorbidities or concurrent prescriptions that raise risk for overdose and recommending more conservative dosing; (2) identifying patients with mental health problems that increase risk of medication abuse and recommending referral to psychiatric care and close monitoring; (3) assisting doctors with complex pharmacologic calculations to reduce the risk of mistakes when initiating, titrating, or switching medications; and (4) presenting relevant information to clinicians in an easy-to-use format. We describe a system evaluation plan that we believe is essential to ensure that deployment of ATHENA-Opioid Therapy leads to improvements in patient safety and increases in guideline-concordant prescribing, and we discuss the limitations of this system for patient safety efforts.